Anesthetic Premedication With a Cannabis Extract (Cannapremed)

Brief description of study

Clinical evidence about the effects of cannabis in a perioperative setting or for the
management of acute pain is rather scarce, mostly consisting of case report-based opinions on
adverse events during or after general anesthesia after smoking cannabis, experimental pain
trials in healthy volunteers, and a few clinical trials using different drugs, dosages and
routes of administration. It is difficult to draw strong conclusions from the available
evidence, that may seem sometimes even contradictory, mainly due -the investigators believeto
the many sources of variability in the study designs (e.g.: heterogeneity of the study
samples, underpowered, unblinding, lack of randomization, timing of the therapeutic
intervention, different experimental pain models, inclusion of different kind of surgical
pain, etc.). Nevertheless, expert's opinion after a critical review of the literature is that
cannabis and cannabinoids may have a beneficial role in the management of acute
post-operative pain and nausea, at least for a selected group of patients and through an
appropriate therapeutic intervention.

Therefore, it seems to us pertinent to carry out an investigation in order to re-evaluate the
issue of perioperative cannabis use through a sufficiently powered and controlled clinical
trial. Some of cannabis effects such as sedation, bronchodilation, dryness of respiratory
secretions, vein dilation, and increase of heart rater without producing hypertension, make
of it an attractive option for pre-medication; while its antiemetic properties and its
analgesic potential without causing respiratory depression may be profitable for the
post-operative period.

Nabiximols seem to be most suitable to our investigation. The co-administration of
tetrahydrocannabinol (THC) with cannabidiol (CBD) may translate into additional therapeutic
benefits with an attenuation of adverse effects. The investigators expect to obtain less
sedation, milder "high", lower incidence of anxiety, tachycardia, and hyperalgesia, as
compared with THC-only acute pain trials.

Treatments will be administered in a double-dummy manner. Identical bottles of Sativex and
placebo should be obtained from the manufacturer (GW Pharmaceuticals). Identical prefilled
vials containing either the active placebo (1 mg midazolam + 1 g acetaminophen) or sodium
chloride 0.9% should be prepared by the hospital pharmacist. To the best of our knowledge, no
clinical studies evaluating the effects of nabiximols on acute pain or in a perioperative
setting have been done to date. Therefore, the investigators estimate a Sativex dose range
that seems reasonable to obtain relevant clinical and a manageable occurrence of adverse
events, mainly based on the recommendations from the manufacturer, on the available
pharmacological data presented in the previous section and on the results of other clinical
trials with a similar design using comparable doses of oral THC. Nevertheless, the first 10
patients will be randomly assigned either to the nabiximols low dose group or to the placebo
control group only. The investigators will proceed with the full four-group randomization
only if no serious adverse events are registered among the 10 first recruited patients.

At the arrival to the operating room, blood samples for baseline levels of cannabinoids will
be drawn at the moment of placing the intravenous line, and the first anxiety assessment
should be done by the examiner/anesthetist. The study drugs will be administered at the
entrance to the O.R. or at the induction room 15 minutes before the induction of anesthesia
(i.e.:). Premedication dose should be calculated to be the equivalent of 10 mg and 20 mg oral
THC for the low and high dose groups, respectively (4, 8 puffs). At the same time, the
prefilled syringe containing either 1 mg midazolam + 1 g acetaminophen or sodium chloride
0.9% will be administered as intravenous bolus. The patients will be immediately connected to
the standard O.R. monitoring.

Induction of general anaesthesia will be done in a standardized fashion with fentanyl 2
g/Kg, propofol 1-4 mg/Kg (and vecuronium 0.1 mg/Kg if intubation is required). For
anaesthetic maintenance, isoflurane 0.7-2% on 1:2 oxygen : nitrous oxide gas mixture, and
fentanyl boluses 1 g/Kg to keep a bispectral index (BIS) between 40 to 60, and a heart rate
and mean arterial pressure between 70-130% from pre-induction baselines. Preemptive
antiemetics (e.g.: granisetron, ondansetron, metoclopramide, dexamethasone, etc.) should not
be given. No additional analgesics should be administered (e.g.: ketorolac or other NSAID's,
dipyrone).

A loading dose of morphine 0.2 mg/Kg will be given before the end of surgery provided that
the patient can maintain spontaneous breathing or pressure support ventilation. Intravenous
morphine patient-controlled analgesia (PCA) will be initiated on the arrival to the recovery
room with boluses of 1 mg and a lockout time of 6 minutes, without background.